PURPOSE:We have assessed the combination of DC-CIK with S-1 plus cisplatin chemotherapy in advanced gastric cancer (AGC) and the role of mutational analysis of circulating tumor DNA (ctDNA) and T-cell receptor (TCR) repertoire in predicting clinical outcomes. PATIENTS AND METHODS:Consecutive patients (n = 63) with AGC were allocated to treatment with S-1 alone, S-1 plus cisplatin, DC-CIK combined with S-1 or DC-CIK combined with S-1 plus cisplatin. The primary endpoints were progression-free survival (PFS) and overall survival (OS) at 1 year; the secondary endpoints were disease control rate and analysis of ctDNA and TCR repertoire. RESULTS:The DC-CIK infusions were well tolerated with no serious adverse events. The disease control rates (CR+PR+SD) were 5.6%, 33.3%, 47.1%, and 76.9% in the S-1 alone, the S-1 plus cisplatin, DC-CIK combined with S-1 and DC-CIK combined with the S-1 plus cisplatin groups, respectively (P = 0.001). After adjusting for competing risk factors, treatment with DC-CIK combined with S-1 plus cisplatin was confirmed to be an independent predictor of PFS and OS (P = 0.001). A decrease in the frequency and number of mutations in ctDNA was observed in 19 patients (63.3%) following the DC-CIK infusions. Decreased ctDNA mutational frequency and restored TCR repertoire were associated with improved PFS and OS (P = 0.001). CONCLUSIONS:DC-CIK combined with S-1 plus cisplatin provided a favorable PFS and OS in patients with AGC and the combination therapy was safe with tolerable toxicities. Clinical efficacy correlated with decreases in ctDNA mutational profiles and restored TCR repertoire.